Severe preeclampsia (sPE) is a placenta-based hypertensive disorder affecting 2 to 7% of all pregnancies. It is the leading cause of fetal and maternal morbidity and mortality worldwide. The Preeclampsia Foundation (2007) estimates the annual economic cost of sPE in the USA to be $7 billion. Presently, the only available cure for this disease is placental and fetal delivery. In severe cases, this disease leads to preterm birth which, in itself, has numerous serious long- term complications. The ultimate goal of this project is to improve pregnancy outcome by ameliorating placental and maternal endovascular function in severe preeclampsia. sPE placentas are characterized by abnormal trophoblast differentiation, which, together with reduced uteroplacental perfusion, results in a hypoxic state leading to abnormal placental secretion of proteins, which in turn contribute to maternal vascular dysfunction, proteinuria and hypertension. The transcription factor and nuclear receptor, peroxisome proliferator-activated receptor-gamma (PPAR?), has recently been found to regulate the transcription factor GCM1, which regulates trophoblast differentiation and is reduced in sPE. PPAR? can be manipulated by drugs of the thiazolidinedione class, which are normally used for the treatment of type II diabetes. Using Rosiglitazone in a rat model of sPE, we have shown great improvements in pregnancy outcome and maternal vascular function. We hypothesize that human trophoblast differentiation is regulated by the PPAR?-GCM1 axis and that it can be induced pharmacologically to improve placental and, in turn, maternal endothelial function. Furthermore, we challenge the current tenet that pathological protein secretion in preeclampsia is primarily caused by hypoxia, and suggest instead that it is driven by abnormal differentiation. This hypothesis will be critically tested by completing the following three specifc aims; 1. We will assess whether PPAR? regulates human trophoblast differentiation by direct regulation of the transcription factor GCM1 as part of a cascade that in turn regulates many other proteins. 2. We will test whether modulation of PPAR? activity will improve placental function in a hypoxic placental explant model of sPE. 3. We will determine whether placental protein secretion can be altered through modulation of PPAR? activity to drive trophoblast differentiation, and whether this, in turn, will improve maternal endothelial function. The efficac of this strategy will be assessed by determining in an angiogenesis assay whether media from pathological tissues treated with PPAR? activating drugs will improve endothelial function. Successful completion of this study will explain new pathways in human placental development and the pathophysiology of preeclampsia.